Three-dimensional brain-like microenvironments facilitate the direct reprogramming of fibroblasts into therapeutic neurons

Biophysical cues can improve the direct reprogramming of fibroblasts into neurons that can be used for therapeutic purposes. However, the effects of a three-dimensional (3D) environment on direct neuronal reprogramming remain unexplored. Here, we show that brain extracellular matrix (BEM) decellular...

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Published inNature biomedical engineering Vol. 2; no. 7; pp. 522 - 539
Main Authors Jin, Yoonhee, Lee, Jung Seung, Kim, Jin, Min, Sungjin, Wi, Soohyun, Yu, Ji Hea, Chang, Gyeong-Eon, Cho, Ann-Na, Choi, Yeeun, Ahn, Da-Hee, Cho, Sung-Rae, Cheong, Eunji, Kim, Yun-Gon, Kim, Hyong-Pyo, Kim, Yonghwan, Kim, Dong Seok, Kim, Hyun Woo, Quan, Zhejiu, Kang, Hoon-Chul, Cho, Seung-Woo
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 01.07.2018
Subjects
Animal models
Brain
Direct conversion
Embryo fibroblasts
Extracellular matrix
Fibroblasts
Hydrogels
Microenvironments
Neurons
Recovery of function
Stroke
Substrates
Therapeutic applications
Transfection
Transplantation
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Summary:Biophysical cues can improve the direct reprogramming of fibroblasts into neurons that can be used for therapeutic purposes. However, the effects of a three-dimensional (3D) environment on direct neuronal reprogramming remain unexplored. Here, we show that brain extracellular matrix (BEM) decellularized from human brain tissue facilitates the plasmid-transfection-based direct conversion of primary mouse embryonic fibroblasts into induced neuronal (iN) cells. We first show that two-dimensional (2D) surfaces modified with BEM significantly increase the generation efficiency of iN cells and enhance neuronal transdifferentiation and maturation. Moreover, in an animal model of ischaemic stroke, iN cells generated on the BEM substrates and transplanted into the brain led to significant improvements in locomotive behaviours. We also show that compared with the 2D BEM substrates, 3D BEM hydrogels recapitulating brain-like microenvironments further promote neuronal conversion and potentiate the functional recovery of the animals. Our findings suggest that 3D microenvironments can boost nonviral direct reprogramming for the generation of therapeutic neuronal cells.
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ISSN:2157-846X
2157-846X
DOI:10.1038/s41551-018-0260-8